The objective of this project is to detect natural and induced mutations in mice for the purpose of providing understanding of the specific molecular events involved in germinal mutation and the effects of these events on the life, form and function of the mammalian organism. Results are relevant to cases of human exposures to mutagens and the potential for increased risk of genetic disease that may accompany mutagen exposure. The problem is approached by detecting mutations at specific biochemical loci with electrophoretic methods, by conducting characterization studies on the mutant genes and gene products, and by examining the animals for expressed physical abnormalities correlated with mutation rate increases and with specific induced-mutant genotypes. The methods have led to successful identification of more than 20 ethylnitrosourea-induced mutants affecting proteins such as malic enzyme, Alpha hemoglobin and phosphoglucomutase, but there is little evidence to suggest that the induction of the detected mutations has been accompanied by any increased incidence of adverse gene expression. Perhaps the best example of a significant genetic disorder (with homology in man) we have discovered by electrophoresis (a Beta-thalassemia) was found to have originated spontaneously. Furthermore, our most recent analysis of skeletal variation shows a reduction in the frequency of naturally occurring variation as the statistically most significant effect of mutagen treatment. The results raise questions as to the extent hypotheses of human genetic risk based upon increased mutation rates are indicative of elevated probabilities for significant genetic damage.